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Encyclopedia > Cyclooxygenase
prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)
Identifiers
Symbol PTGS1
Entrez 5742
HUGO 9604
OMIM 176805
RefSeq NM_080591
UniProt P23219
Other data
EC number 1.14.99.1
Locus Chr. 9 q32-q33.3
prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)
Identifiers
Symbol PTGS2
Entrez 5743
HUGO 9605
OMIM 600262
RefSeq NM_000963
UniProt P35354
Other data
EC number 1.14.99.1
Locus Chr. 1 q25.2-25.3

Cyclooxygenase (COX) is an enzyme (EC 1.14.99.1) that is responsible for formation of important biological mediators called prostanoids (including prostaglandins, prostacyclin and thromboxane). Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain; this is the method of action of well-known drugs such as aspirin and ibuprofen. The Entrez logo The Entrez Global Query Cross-Database Search System allows access to databases at the National Center for Biotechnology Information (NCBI) website. ... Look up Hugo in Wiktionary, the free dictionary. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... National Center for Biotechnology Information logo The National Center for Biotechnology Information (NCBI) is part of the United States National Library of Medicine (NLM), a branch of the National Institutes of Health. ... Swiss-Prot is a curated biological database of protein sequences created in 1986 by Amos Bairoch during his PhD and developed by the Swiss Institute of Bioinformatics and the European Bioinformatics Institute. ... The Enzyme Commission number (EC number) is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze. ... Short and long arms Chromosome. ... Chromosome 9 is one of the 23 pairs of chromosomes in humans. ... The Entrez logo The Entrez Global Query Cross-Database Search System allows access to databases at the National Center for Biotechnology Information (NCBI) website. ... Look up Hugo in Wiktionary, the free dictionary. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... National Center for Biotechnology Information logo The National Center for Biotechnology Information (NCBI) is part of the United States National Library of Medicine (NLM), a branch of the National Institutes of Health. ... Swiss-Prot is a curated biological database of protein sequences created in 1986 by Amos Bairoch during his PhD and developed by the Swiss Institute of Bioinformatics and the European Bioinformatics Institute. ... The Enzyme Commission number (EC number) is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze. ... Short and long arms Chromosome. ... Chromosome 1 is, by convention, the designation for the largest human chromosome. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... The Enzyme Commission number (EC number) is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze. ... Prostanoid is the term used to describe three classes of eicosanoids: the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes (mediators of vasoconstriction) and the prostacyclins (active in the resolution phase of inflamation. ... Chemical structure of prostaglandin E1 (PGE1). ... Prostacyclin is a member of the family of lipid molecules known as eicosanoids. ... Thromboxane is a member of the family of lipids known as eicosanoids. ... An abscess on the skin, showing the redness and swelling characteristic of inflammation. ... “Hurting” redirects here. ... Aspirin, or acetylsalicylic acid (IPA: ), (acetosal) is a drug in the family of salicylates, often used as an analgesic (to relieve minor aches and pains), antipyretic (to reduce fever), and as an anti-inflammatory. ... Ibuprofen (INN) (IPA: ) (from the earlier nomenclature iso-butyl-propanoic-phenolic acid) is a non-steroidal anti-inflammatory drug (NSAID) originally marketed as Nurofen and since under various trademarks including Act-3, Advil, Brufen, Dorival, Herron Blue, Panafen, Motrin, Nuprin and Ipren or Ibumetin (Sweden), Ibuprom (Poland), IbuHEXAL, Moment (Italy...

Contents

Physiology

See also prostaglandin and eicosanoid for more details Chemical structure of prostaglandin E1 (PGE1). ... In biochemistry, eicosanoids are a class of oxygenated hydrophobic molecules that largely function as autocrine and paracrine mediators. ...


COX converts arachidonic acid (AA, an ω-6 PUFA) to prostaglandin H2 (PGH2), the precursor of the series-2 prostanoids. The enzyme contains two active sites: a heme with peroxidase activity, responsible for the reduction of PGG2 to PGH2, and a cyclooxygenase site, where arachidonic acid is converted into the hydroperoxy endoperoxide prostaglandin G2 (PGG2). The reaction proceeds through H atom abstraction from arachidonic acid by a tyrosine radical generated by the peroxidase active site. Two O2 molecules then react with the arachidonic acid radical, yielding PGG2. Arachidonic acid (AA) is an omega-6 fatty acid 20:4(ω-6). ... Omega-6 fatty acids are fatty acids where the term omega-6 signifies that the first double bond in the carbon backbone of the fatty acid, counting from the end opposite the acid group, occurs in the sixth carbon-carbon bond. ... A polyunsaturated fatty acid (PUFA) is a class of unsaturated fat that contains more than one double bond. ... Chemical structure of prostaglandin E1 (PGE1). ... Prostanoid is the term used to describe three classes of eicosanoids: the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes (mediators of vasoconstriction) and the prostacyclins (active in the resolution phase of inflamation. ... Structure of Heme b A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. ... Glutathione Peroxidase 1 A peroxidase (eg. ... Glutathione Peroxidase 1 A peroxidase (eg. ...


Currently three COX isoenzymes are known—COX-1, COX-2 and COX-3. COX-3 is a splice variant of COX-1 which retains intron one and has a frameshift mutation, thus some prefer the name COX-1b or COX-1 variant (COX-1v).[1] Isozymes, (or isoenzymes) are isoforms (closely related variants) of enzymes. ... In genetics, splicing is a modification of genetic information after transcription, in which introns of precursor messenger RNA (pre-mRNA) are removed and exons of it are joined. ... Diagram of the location of introns and exons within a gene. ... A frameshift mutation (also called a frameshift or a framing error) is a genetic mutation that inserts or deletes a number of nucleotides that is not evenly divisible by three from a DNA sequence. ...


Different tissues express varying levels of COX-1 and COX-2. Although both enzymes act basically in the same fashion, selective inhibition can make a difference in terms of side-effects. COX-1 is considered a constitutive enzyme, being found in most mammalian cells. More recently it has been shown to be upregulated in various carcinomas and to have a central role in tumorigenesis. COX-2, on the other hand, is undetectable in most normal tissues. It is an inducible enzyme, becoming abundant in activated macrophages and other cells at sites of inflammation. Adaptive enzyme is an enzyme that is present in the cell only under conditions in which it is clear of adaptive value. ... A macrophage of a mouse stretching its arms to engulf two particles, possibly pathogens Macrophages (Greek: big eaters, makros = long, phagein = eat) are white blood cells, more specifically phagocytes, acting in the nonspecific defense as well as the specific defense system of vertebrate animals. ...


Both COX-1 and -2 also oxygenate two other essential fatty acids – DGLA (ω-6) and EPA (ω-3) – to give the series-1 and series-3 prostanoids, which are less inflammatory than those of series-2. DGLA and EPA are competitive inhibitors with AA for the COX pathways. This inhibition is a major mode of action in the way that dietary sources of DGLA and EPA (e.g. borage, fish oil) reduce inflammation. Dihomo-gamma-linolenic acid (DGLA) is 20-carbon ω-3 fatty acid. ... Eicosapentaenoic acid (EPA or also icosapentaenoic acid) is an omega-3 fatty acid. ... An abscess on the skin, showing the redness and swelling characteristic of inflammation. ... In biochemistry there are three ways in which certain chemical substances may reduce or prevent the activities of enzymes: competitive, non-competitive and uncompetitive inhibition. ... Binomial name Borago officinalis L. Borage (Borago officinalis), also known as starflower, is an annual herb native to central and eastern Europe. ... Fish Oil is oil derived from fishes. ...

Enzyme cyclooxygenase (box: first step in creating prostaglandins from fatty acids) (more details...)
Enzyme cyclooxygenase (box: first step in creating prostaglandins from fatty acids) (more details...)
Cyclooxygenase reaction mechanism

Image File history File links No higher resolution available. ... Image File history File links No higher resolution available. ... Image File history File links Size of this preview: 683 × 600 pixel Image in higher resolution (1230 × 1080 pixel, file size: 14 KB, MIME type: image/gif) Cycloxygenase reaction mechanism. ... Image File history File links Size of this preview: 683 × 600 pixel Image in higher resolution (1230 × 1080 pixel, file size: 14 KB, MIME type: image/gif) Cycloxygenase reaction mechanism. ...

Pharmacology

In terms of their molecular biology, COX-1 and COX-2 are of similar molecular weight (approximately 70 and 72 kDa respectively), and having 65% amino acid sequence homology and near-identical catalytic sites. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of isoleucine at position 523 in COX-1 with valine in COX-2. The relatively smaller Val523 residue in COX-2 allows access to a hydrophobic side-pocket in the enzyme (which Ile523 sterically hinders). Drug molecules, such as DuP-697 and the coxibs derived from it, bind to this alternative site and are considered to be selective inhibitors of COX-2. The unified atomic mass unit (u), or dalton (Da), is a small unit of mass used to express atomic masses and molecular masses. ... Isoleucine is one of the 20 natural amino acids, and is coded for in DNA. Its chemical composition is identical to that of leucine, but the arrangement of its atoms is slightly different, resulting in different properties. ... Valine is an amino acid that cannot be synthesized by humans, so it is considered an essential amino acid for human life. ... In chemistry, hydrophobic or lipophilic species, or hydrophobes, tend to be electrically neutral and nonpolar, and thus prefer other neutral and nonpolar solvents or molecular environments. ...


Classical NSAIDs

The main COX inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs). Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. ...


The classical COX inhibitors are not selective (i.e. they inhibit all types of COX), and the main adverse effects of their use are peptic ulceration and dyspepsia. It is believed that this may be due to the "dual-insult" of NSAIDs - direct irritation of the gastric mucosa (many NSAIDs are acids), and inhibition of prostaglandin synthesis by COX-1. Prostaglandins have a protective role in the gastrointestinal tract, preventing acid-insult to the mucosa. A benign gastric ulcer (from the antrum) of a gastrectomy specimen. ... Chemical structure of prostaglandin E1 (PGE1). ...


Newer NSAIDs

Selectivity for COX-2 can halve the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this drug class. Cox-2-selectivity does not seem to affect other side-effects of NSAIDs (most notably an increased risk of renal failure), and some results have aroused the suspicion that there might be an increase in the risk for heart attack, thrombosis and stroke by a relative increase in thromboxane. Rofecoxib (brand name Vioxx) was taken off the market in 2004 because of these concerns. Some other COX-2 selective NSAIDs, such as celecoxib and etoricoxib, are still on the market. Celecoxib (INN) (IPA: ) is a non-steroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial adenomatous polyposis. ... Rofecoxib (IPA: ) is a nonsteroidal anti-inflammatory drug (NSAID) developed by Merck & Co. ... Renal failure is the condition in which the kidneys fail to function properly. ... Acute myocardial infarction (AMI or MI), more commonly known as a heart attack, is a disease state that occurs when the blood supply to a part of the heart is interrupted. ... Thrombosis is the formation of a clot or thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system. ... For other uses, see Stroke (disambiguation). ... Thromboxane is a member of the family of lipids known as eicosanoids. ... Rofecoxib (IPA: ) is a nonsteroidal anti-inflammatory drug (NSAID) developed by Merck & Co. ... Rofecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that was used in the treatment of osteoarthritis, acute pain conditions, and dysmenorrhoea. ... Celecoxib (INN) (IPA: ) is a non-steroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial adenomatous polyposis. ... Etoricoxib (brand name Arcoxia®) is a new COX-2 selective inhibitor from Merck & Co. ...


Non-NSAID COX inhibition

Acetaminophen, also known as paracetamol, reversibly inhibits COX-3. COX-3 produces prostanoids in the brain, but does not participate in eicosanoid signalling in inflammation. Acetaminophen thereby interferes with the perception of pain. Since it has no effect on inflammation, it is not classed as an NSAID.[2][3] Acetaminophen (USAN) or paracetamol (INN), is a popular analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. ...


Cardiovascular side effects of COX inhibitors

COX-2 inhibitors have been found to increase the risk of atherothrombosis even with short term use. A 2006 analysis of 138 randomised trials and almost 150 000 participants [4] showed that selective COX-2 inhibitors are associated with a moderately increased risk of vascular events, mainly due to a twofold increased risk of myocardial infarction, and also that high dose regimens of some traditional NSAIDs such as diclofenac and ibuprofen are associated with a similar increase in risk of vascular events. Thrombosis is the formation of a clot or thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system. ... Acute myocardial infarction (AMI or MI), more commonly known as a heart attack, is a disease state that occurs when the blood supply to a part of the heart is interrupted. ... Diclofenac (marketed as Voltaren®, Voltarol®, Diclon®, Dicloflex® Difen and Cataflam®) is a non-steroidal anti-inflammatory drug (NSAID) taken to reduce inflammation and an analgesic reducing pain in conditions such as in arthritis or acute injury. ... Ibuprofen (INN) (IPA: ) (from the earlier nomenclature iso-butyl-propanoic-phenolic acid) is a non-steroidal anti-inflammatory drug (NSAID) originally marketed as Nurofen and since under various trademarks including Act-3, Advil, Brufen, Dorival, Herron Blue, Panafen, Motrin, Nuprin and Ipren or Ibumetin (Sweden), Ibuprom (Poland), IbuHEXAL, Moment (Italy...


References

  1. ^ Chandrasekharan, N.V., Dai, H., Roos, K.L.T. et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proceedings of the National Academy of Sciences of the United States of America 99(21):13926-31, (2002). PMID 12242329.
  2. ^ Warner, Timothy D. and Mitchell, Jane A. (October 8, 2002). "Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum?". PNAS 99 (21): 13371-13373. DOI:10.1073/pnas.222543099. Retrieved on 2007-01-05. 
  3. ^ Soberman, Roy J. and Christmas, Peter (2003). "The organization and consequences of eicosanoid signaling". J. Clin. Invest 111: 1107-1113. DOI:doi:10.1172/JCI200318338. Retrieved on 2007-01-05. 
  4. ^ Kearney PM, Baigent C, Godwin J, Halls H, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006 Jun 3;332(7553):1302-8. PMID 16740558

A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 5 is the 5th day of the year in the Gregorian calendar. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 5 is the 5th day of the year in the Gregorian calendar. ...

Further reading

  • Pedro J. Silva, Pedro A. Fernandes and Maria J. Ramos (2003) A theoretical study of radical-only and combined radical/carbocationic mechanisms of arachidonic acid cyclooxygenation by prostaglandin H synthase. Theoretical Chemistry Accounts, 110, 345-351.

See also

  • COX-2 selective inhibitor

This article needs cleanup. ...

External links

  • The Cyclooxygenase Protein
  • MeSH Cyclooxygenase

  Results from FactBites:
 
Cyclooxygenase Isoenzymes and Newer Therapeutic Potential for Selective COX-2 Inhibitors (3760 words)
Cyclooxygenase (COX), also known as prostaglandin G/H synthase, is a membrane-bound enzyme responsible for the oxidation of arachidonic acid to prostaglandins that was first identified over 20 years ago.
Cyclooxygenase (COX), the enzyme that catalyses the synthesis of cyclic endoperoxides from arachidonic acid to form prostaglandins (PG), was isolated in 1976 and cloned in 1988 (1).This membrane-bound hemo- and glycoprotein has a molecular weight of 71 kDa, and is found in the greatest amounts in the endoplasmic reticulum of prostanoid forming cells (2).
Cyclooxygenase ­ 2 expression is increased in frontal cortex of Alzheimer 's disease brain.
  More results at FactBites »

 
 

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